The reversible histone acetylation taking place on the ε-amino group of the lysine residue in the histone N-terminal section mediates important conformational modifications within the nucleosomes. These modifications affect DNA capability to access transcription factors as well as genic expression (Curr. Opin. Genet. Dev. 1998, 8, 173-178). Two classes of enzymes are involved in histone acetylation: histone acetyltransferases (HATs), which catalyse histone acetylation by acting as transcription co-activators, and histone deacetylases (HDACs); the latter enzymes are recruited at the level of promoter regions by transcription repressors and co-repressors such as Sin3, SMRT, and N-CoR, leading to the formation of hypoacetylated histones and transcription silencing (Trends Biochem. Sci. 2000, 25, 619-623). The aberrant recruitment of histone deacetylases through oncogenic proteins, or the disturbed balance of activities of histone acetyltransferases and histone deacetylases in normal cells are involved in a number of pathologies:
first of all, in tumor diseases (Oncogene 2001, 20, 7204-7215, 7186-7203, 3116-3127; Nature 1998, 391, 815-818; Mol. Cell. Biol. 1998, 18, 7176-7184).
in several non-tumor diseases:
Nervous System:
Huntington's disease (J Neurosci 23, 9418-27 (2003); Proc Natl Acad Sci USA 100, 2041-6 (2003)), diseases caused by triplette amplifications (Curr Med Chem 10, 2577-87 (2003); Curr Biol 12, R141-3 (2002)), neuroprotection against degenerative diseases (FEBS Lett 542, 74-8 (2003); ischemia (J Neurochem 89, 1358-67 (2004)), oxidative stress (Proc Natl Acad Sci USA 100, 4281-6 (2003)), inflammatory responses of the nervous system (J Neurochem 87, 407-16 (2003)), epilepsy (Epilepsia 45, 737-44 (2004), J Neurosci 22, 8422-8 (2002)), diseases caused by protein aggregates (Curr Biol 14, 488-92 (2004)).
Infection:
HIV (Mol Cell Biol 23, 6200-9 (2003), Embo J 15, 1112-20 (1996), Biochem Pharmacol 68, 1231-8 2004), Aids 18, 1101-8 (2004)), malaria, leishmaniosis, infections caused by protozoa, fungi, phytotoxic agents, virus, parasites.
Immune System:
autoimmune diseases (Blood 101, 1430-8 (2003)), chronic host-directed immune reaction (Proc Nat Acad Sci USA 101, 3921-6 (2004)).
Heart:
hypertrophy and cardiac disorders (J Clin Invest 112, 863-71 (2003), Novartis Found Symp 259, 132-41, discussion 141-5, 163-9 (2004), J Clin Invest 112, 824-6 (2003)).
Muscular Apparatus:
skin fibrotic disease (Exp Cell Res 278, 184-97 (2002)), fibrosis (Hepatology 29, 858-67 (1999)), spinal and bulbar muscular atrophy, (Hum Mol Genet 13, 1183-92 (2004)).
Psychic System:
bipolar disorders (Nature 417, 292-5 (2002)), psychiatric disorders (Crit Rev Neurobiol 15, 121-42 (2003)), X-fragile syndrome (BMC Mol Biol 4, 3 (2003), Hum Mol Genet 8, 2317-23 (1999)).
Others:
arthritis (Mol Ther 8, 707-17 (2003)), renal diseases (J Clin Invest 111, 539-52 (2003)), psoriasis (Curr Drug Targets Inflamm Allergy 3, 213-9 (2004)), intestinal diseases, colitis (Wien Klin Wochenschr 114, 289-300 (2002)), beta thalassemy (Expert Opin Investig Drugs 10, 925-34 (2001)), respiratory diseases (Am J Respir Crit Care Med 167, 813-8 (2003)), Rubinstein-Taybi syndrome (Neuron 42, 947-59 (2004)).
Histone deacetylases inhibitors, such as the natural products tricostatin A (TSA), trapoxin (TPX), and depsipeptide FK-228, short chain fatty acids, sodium butyrrate, phenylbutyrrate and valproate, hydroxamic acid, hydroxamates such as the suberoylanilide hydroxamic acid (SAHA), pyroxamide, scriptaid, oxamflatin, NVP-LAQ824, cyclic peptides containing hydroxamic acid (CHAPs), and the benzamide MS-275 strongly promote growth interruption, differentiation and apoptosis in a number of transformed cells in culture and in animal models (Curr. Opin. Oncol. 2001, 13, 477-483). Among them, sodium phenylbutyrate (alone or in combination), depsipeptide, SAHA, pyroxamide, NVP-LAQ824, MS-275, are in clinical phase I and/or II for the treatment of several cancerous diseases (Nat. Rev. Drug Discov. 2002, 1, 287-299). Nevertheless their clinical utility is restricted by toxicity problems (TSA, CHAPs, MS-275), low stability (TSA, trapoxin), low solubility (TSA), low potency and lack of selectivity (butyrates and analogues) (Anti-Cancer Drugs 2001, 13, 1-13).
WO 04/063169 discloses hydroxamic acid derivatives as HDAC inhibitors with the following general formula:
with R1 is a N-containing heterocyclic ring optionally substituted with one or more suitable groups, R2 is hydroxylamino, R3 is hydrogen or a suitable substituent, L1 is —(CH2)n— with n an integer of 0 to 6, optionally substituted with one or more suitable substitutents and wherein one or more methylene(s) may be replaced with suitable heteroatom(s); L2 is a lower alkylene chain.
WO 03/087066 describes hydroxamic acid derivatives and their use as histone deacetylase inhibitors with the following formula
where A is an optionally substituted phenyl or aromatic heterocyclic group; m and n independently an integer from 0 to 4; and X is a moiety having a structure selected from
where R2 is hydrogen or optionally substituted C1-C4 alkyl.
WO 02/22577 discloses the following hydroxamic acid derivatives as deacetylase inhibitors of general formula
where R1 is hydrogen, halogen or a C1-C6 alkyl chain, R2 is selected from H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl etc.; R3 and R4 are independently selected from hydrogen, C1-C6 alkyl, acyl or acylaminoR5 is selected from hydrogen, C1-C6 alkyl and others; n1, n2 and n3 are an integer from 0 to 6, X and Y are selected from hydrogen, halogen, C1-C4 alkyl etc.
WO 01/38322 describes histone deacetylase inhibitors of the general formulaCy-L1-Ar—Y1—C(O)—NH—Zwhere Cy is an optionally substituted cycloalkyl, aryl, heteroaryl or heterocyclyl ring; L1 is —(CH2)m—W with m an integer from 0 to 4, W is selected among others from C(O)NH—, S(O)2—NH—; Ar is an optionally substituted arylene ring, wherein said arylene may be optionally fused to an aryl or heteroaryl ring, Y1 is a bond or a saturated alkylene chain; Z is among other groups O-M, wherein M is hydrogen or a suitable pharmaceutical cation ion.
WO 95/13264 discloses hydroxamic acid derivatives of general formula
wherein R1 represents among other groups phenyl or aryloxyphenyl; L is C1-C8 alkylene, C2-C8 alkenylene, (CH2)m—O— (wherein m is an integer from 0 to 4), or —CO—; n is 0 or 1; R2 is hydrogen, C1-C4 alkyl or arylalkyl; M is, hydrogen, alkoyl, alkoxycarbonyl; and their use as medicinal having the effect of suppressing smooth muscle growth and being usable as a vascular wall thickening preventive, a post-PTCA retenosis preventive and even an antiarterosclerotic agent.
Mai et al. describe in J. Med. Chem. 2001, 44, 2069-2072, J. Med. Chem. 2002, 45, 1778-1784, J. Med. Chem. 2003, 46, 512-524, J. Med. Chem. 2003, 46, 4826-4829, J. Med. Chem. 2004, 47, 1098-1109, J. Med. Chem. 2004, 47, 1351-1359 and J. Med. Chem. 2005, 48, 3344-3353 pyrrolyl hydroxamide derivatives as selective HDAC inhibitors.
Further HDAC inhibitors are discussed in Expert Opin. Ther. Patents 2004, 14(6), 791-804). Histone deacetylases inhibitors were also identified with different affinities with respect to specific subclasses of histone deacetylases (HD2, HD1-A, HD1-B): the discriminating ability among the various subclasses of histone deacetylases leads to important consequences: i.e. the elimination of side effects and/or the activity towards specific forms of tumor.
However, none of the aforementioned compounds has so far shown a fully satisfactory profile. It is thus still desired to find new histone deacetylases inhibitors having useful antitumor properties, adequate selectivity and stability of action; also, the search is open for new inhibitors having high activity on histone deacetylases, possibly showing a higher activity with respect to specific subclasses thereof.